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Chapter 111 Principles of Red Blood Cell Transfusion 1707

Discoveries during the past two decades have raised clinical Citrate
concern regarding the efficacy and risk of RBC transfusion. Changes
within the RBC and its supernatant during RBC storage have been Infusion of large volumes of blood with citrate anticoagulant over a
associated with reduced tissue oxygenation and other adverse effects short period may cause plasma citrate levels to reach the toxic range.
in patients receiving RBC components stored for extended periods. The primary concern is the cardiovascular effects of hypocalcemia
The biochemical, structural, and functional changes are collectively caused by chelation of calcium by citrate. The risk of citrate toxicity
termed the red cell storage lesion. The alterations found with the is exacerbated by liver dysfunction or liver immaturity. Despite these
storage lesion along with the clinical implications will be discussed theoretical considerations, there is little documented evidence of
in this section. clinical citrate toxicity, which can usually be prevented by slower
infusion. If large amounts of blood have to be infused over a very
short period, administration of calcium gluconate can be considered,
BIOCHEMICAL CHANGES ASSOCIATED WITH but whether the benefits justify the risk is controversial.
RED BLOOD CELL STORAGE
Potassium
Adenosine Triphosphate Levels
Another issue with prolonged storage is the excess potassium in the
ATP levels appear to be a major determinant of red cell viability. The RBC supernatant that could potentially cause cardiac arrhythmias.
drop in cellular ATP levels during storage has been correlated with At a storage temperature of 4°C, the red cell sodium-potassium pump
increased cell rigidity and with loss of membrane lipid, leading to is essentially nonfunctional, and intracellular and extracellular levels
decreased red cell life span. For this reason, most efforts to extend gradually equilibrate. In addition, hemolysis results in increased
RBC storage have focused on ways to maintain intracellular ATP potassium in the supernatant. However, because the total volume of
levels. First, dextrose was introduced into the citrate solution (citrate- plasma in RBC concentrates is low (approximately 70 mL), the total
phosphate-dextrose [CPD]: 21 day shelf life), and then adenine was potassium burden is only approximately 5.5 mEq at product expira-
added (CPDA-1: 35 day shelf life). Three additive solutions contain- tion. Practically speaking, the potassium load is rarely a clinical
ing additional dextrose and adenine (Nutricel, or AS-3) or dextrose problem except in the setting of preexisting hyperkalemia and renal
and adenine plus mannitol (Adsol, or AS-1) and (Optisol, or AS-5) failure in adults. In children with rapid or massive transfusions,
allow extension of the maximum storage time to 42 days (Table hyperkalemic cardiac arrest is more commonly recognized. In these
111.3). The majority of today’s RBC supply is stored in an additive situations, fresher units of RBCs or washed RBCs can be used.
solution.
Di(2-ethylhexyl)phthalate
2,3-Diphosphoglycerate Levels
Since their introduction in the 1960s, plastic blood bags used for
Stored RBCs must also maintain their capacity to deliver oxygen. It storing RBCs have been made from polyvinylchloride containing the
was not until 1967 that the central role of 2,3-DPG in releasing lipophilic plasticizer di(2-ethylhexyl)phthalate (DEHP), which
oxygen from oxyhemoglobin was recognized. Attention was then confers pliability. The safety of DEHP has been questioned for years
focused on ways to maintain high levels of 2,3-DPG in stored RBCs. owing to its tendency to leach from the bag and to be present at levels
The first anticoagulant introduced on a large scale, acid citrate- of 50–70 mg/L in stored RBCs. The storage of RBCs in bags made
dextrose, was ineffective because of its low initial pH; however, the of polyvinyl chloride plasticized with DEHP has caused more recent
subsequently developed CPD, with its higher initial pH and slower concern because of the reported association between DEHP exposure
fall in pH, was superior. CPDA-1 and additive solutions have not and impaired development of the male genital tract. One of the
further improved 2,3-DPG maintenance. Although 2,3-DPG deple- benefits of using DEHP for RBC storage is the prevention of hemo-
tion of stored RBCs is known to decrease oxygen delivery, the clinical lysis. DEHP leaches out from the plastic bag and intercalates and
significance of this finding is unclear. 2,3-DPG levels in stored RBCs stabilizes the red cell membrane. Shorter storage lessens the load of
are rapidly regenerated in vivo, rising to greater than 50% of normal DEHP delivered to the recipient. Although there are potential
within several hours and to normal within 24 hours of transfusion. replacement plasticizers, DEHP is most commonly used since the
Although a patient with normal cardiac status should be able to exposure to DEHP through transfusion is generally felt to be less
compensate by increasing cardiac output to maintain normal oxygen than other environmental exposures.
delivery until 2,3-DPG levels are regenerated, an improvement in
2,3-DPG preservation in stored RBCs is still desirable.
Storage Length of Red Blood Cells

TABLE Biochemical Changes in Stored Red Blood Cells Current Status
111.3
The current expiration time of an RBC unit stored in an additive
Variable CPDA-1 CPDA-1 Adsol Fresh 35 Days 35 Days
solution is 42 days. The allowable storage time is regulated by the
In vivo survival (at 100 <71.0 <88.0 FDA and requires: 1) the recovery of at least 75% of red cells trans-
24 hours) (%) fused twenty-four hours after infusion, and 2) less than 1% hemolysis,
pH <7.5 <6.7 <6.7 both at the end of the storage limit. There is no criterion based on
the clinical ability of transfused red cells to oxygenate tissue. The
ATP (% initial) 100 <45.0 <76.0
2011 National Blood Collection and Utilization Survey reported that
2,3-DPG (% initial) 100 <10.0 <10.0 the mean age of RBC units at transfusion was 17.9 days.
Plasma K (mEq/L) 5.1 <78.5 <49.0 Many variables affect the age of a specific RBC unit at transfusion.
+
CPDA-1, Citrate phosphate dextrose adenine-1; DPG, 2,3-diphosphoglycerate. The blood group of the unit will impact the length of storage. Group
Data from Zuck TF, Bensinger TA, Peck CC, et al: The in vivo survival of red O units tend to be issued quickly due to their universal compatibility;
cells stored in modified CPD with adenine: Report of a multi-institutional as a result, Group O units are often issued with a shorter age. Group
cooperative effort. Transfusion 17:34, 1977; and Moore GL, Peck CC, Sohmer B and AB tend to be stored the longest. Transfusion service policies
RR, Zuck TF: Some properties of blood stored in anticoagulant CPDA-1 will also affect the overall age of RBC units at the time of transfusion.
solution: A brief summary. Transfusion 21:135, 1981.
Busy tertiary care hospitals tend to transfuse some of the oldest units